Regulation of Ocular Hypotensive Actions of Cannabinoids by β-Adrenoreceptors

Intraocular pressure (IOP) is the primary risk factor for glaucoma. Cannabinoid (CB) agonists have long been known to decrease IOP; however, the specific mechanism by which CBs generate this ocular hypotensive effect remains unknown. Hudson et al. evaluated the ocular hypotensive role of CB1 and CB2 receptors and their connection with β-adrenoreceptors using genetic receptor knockout models and a pharmacological approach. CB agonists, β-adrenoceptor (βAR) antagonists, or βAR agonists decreased IOP in wild-type and CB2(−/−) mice. In contrast, none of these agents was found to reduce IOP in βAR(−/−) or CB1(−/−) mice. This study provides the first evidence that CB agonists do not reduce IOP in βAR(−/−) mice, demonstrating the direct involvement of βARs in the ocular hypotensive actions of CBs. Desensitization of βARs and depletion of catecholamines in wild-type mice also eliminated the ability of CB agonists to reduce IOP. Colocalization of CB1 receptors and presynaptic adrenergic inputs also implicate that CB agonist inhibit presynaptic norepinephrine release. These studies suggest that βARs are required for the ocular hypotensive properties of CBs and that CBs reduce IOP by acting as indirect sympatholytics and inhibiting norepinephrine release within the eye.